The invention relates to novel xanthine derivatives having at least one alkynol side chain in position 1 or 7 of the xanthine framework, processes for their preparation and their use as active substances in pharmaceuticals, in particular for the treatment and/or prophylaxis of cerebrovascular disorders characterized by damage caused by ischemia and subsequent necrotic destruction of nerve cells (neurons).
Postischemic neuronal cell death and the fatal functional deficits caused thereby, with correspondingly serious neurological and/or psychological symptoms, are the common clinical picture of a large number of cerebrovascular disorders. These include, for example, stroke; transient ischemic attacks (TIA); multiinfarct dementia, dementia of the mixed type with vascular and degenerative (Alzheimer) components; spinal cord damage; brain trauma as a result of head injuries; and neuronal damage after cardiac arrest, (neonatal) asphyxia and resuscitation, and vascular surgical operations (for example bypass operations) in the region of the main arteries supplying the brain.
In clinical practice it is stroke which predominates, also called cerebrovascular accident, apoplexy, cerebral apoplexia or apoplectic insult. It is the basic cause of about 15% of all deaths (Pschyrembel, Klinisches Worterbuch [Clinical Dictionary] Walter de Gruyter-Verlag, 255th edition, 1986, page 105) and is thus in third place after heart disease and cancers in the statistics of the causes of deaths (Pharmazeutische Zeitung 1994, 139/31: 2482-2483). Women and men are equally affected, there being a drastic increase in morbidity after the 6th decade. The incidence is currently about 0.8% of the world population with a continuous increase in prevalence, especially in industrialized countries because the average life expectancy is continuously increasing there.
If a stroke is survived, it usually leaves behind persistent damage, for example paralysis, speech disturbances and/or convulsions, which make it necessary for the patients to receive continuing intensive care with an enormous burden of suffering, also for the relatives, and an immense burden of costs on the health services. Thus, the cost for the treatment and aftercare of stroke patients in the USA alone is currently estimated at 20 billion U.S. dollars annually. In addition, approximately 10% of all surviving victims of stroke suffer another cerebrovascular accident during the first year thereafter, with a considerably worsened prognosis.
Hence the development and clinical establishment of an effective drug therapy which reduces both the acute mortality and the extent of the neurological deficits and the rate of recurrence, and thus distinctly improves the quality of life after a stroke, represent a huge challenge with social and medical significance for pharmaceutical research.
The cause of stroke is always a disturbance of the circulation, associated with oxygen deficiency, in a localized region of the brain. The signs and symptoms are characterized by disturbances of consciousness as far as coma, frequently spastic hemiplegia, symptoms of a wide variety of central motor and sensory deficits and focal or generalized convulsions. A distinction has to be made in the etiology between cerebral hemorrhage or encephalorrhagia, which is associated with high mortality (initial hemorrhagic insult; about 15% of cases; frequently as massive bleeding) after rupture of a vessel, mainly of the striolenticular arteries as a consequence of hypertension, arteriosclerosis or intracranial aneurysm as basic disorder, and cerebral infarct or encephalomalacia (initial non-hemorrhagic insult; about 85% of cases) with development of an ischemic focus of softening (necrosis) caused either by functional ischemia, inter alia as a result of a hypotensive crisis, usually of cardiac origin, or mainly due to progressive or persistent ischemia resulting from stenosing or obliterating vascular processes of arteriosclerotic, thrombotic and embolic origin in the region of the extra- and/or intracranial arteries, preferentially located in the internal carotid, middle cerebral and vertebral artery. The symptoms of encephalomalacia, which are rare and develop slowly, are referred to as "progressive stroke".
Preliminary signs that a cerebrovascular accident is threatening are regarded as being the frequently recurring transient ischemic attacks (TIA) lasting from 2 to 15 minutes with temporary symptoms of neurological deficit, whose origin is a transient, localized disturbance of blood flow caused by stenosis or by microembolisms, and which resolve within minutes to 24 hours at the most with complete recovery. Effective treatment of these ischemic attacks would therefore be very important for the prophylaxis of stroke.
Epidemiologically confirmed risk factors which favor the development of cerebral ischemias are, for example, arterial hypertension, hyperlipidemia, hyperuricemia, diabetes mellitus, rheological blood disorders, heart failure and the taking of hormonal contraceptives (Pschyrembel, Klinisches Worterbuch [Chemical Dictionary], Walter de Gruyter-Verlag, 255th edition, 1986, page 1840).
The therapy currently applied to cerebrovascular disorders is confined to measures which have no direct effect on the cerebral ischemia (Schweiz. Med. Wochenschr. 1994, 124/45: 2005-2012). The only aim of the therapy is to maintain an adequate perfusion in the still intact area on the margin of the ischemic focus in order, at best, to limit the progressive infarction of the brain tissue. A predominant part is played, when the indication is appropriate, by vascular surgical procedures such as intramural desobliteration or the bridging of vascular stenoses by an extra/intracranial bypass, although these are associated with a relatively high operative risk. In particular, the medical procedures available at present do not permit causal treatment; on the contrary they are directed exclusively at eliminating the signs and symptoms. This includes primarily ensuring adequate cardiac function by administration of digitalis glycosides and antiarrhythmics, controlling the blood pressure, eliminating metabolic disturbances, mainly in the electrolyte and glucose balance, and preventing further thrombotic foci by antithrombotic therapy with acetylsalicylic acid or heparin, whereas anticoagulants of the vitamin K antagonist type (coumarins) are contraindicated because of the increased risk of hemorrhage. In addition, elimination of previously known risk factors is also thought to be of therapeutic importance.
Acute drug treatment of cerebral ischemia thus represents an as yet unsolved clinical problem (Ann. Radiol. 1994, 37/1-2: 132-135). This is also the conclusion of a recently published critical analysis of all the major clinical therapeutic studies carried out to date (Lancet 1992, 339/8792: 537-539), it being emphasized once again that reducing the mortality and limiting the neurological sequelae in the survivors are criteria of equal importance for assessing the result of treatment.
Clinicians are therefore demanding new therapeutic ideas aimed more at the causes. Promising approaches to this are provided by the complex pathophysiological processes at the vascular and cellular level which, in the form of a vicious circle, are at the basis of the progressive course of the acute cerebral ischemia. According to the current state of knowledge, the pathogenetic path from cellular ischemia and cell death is characterized by a cascade of physiological and biochemical processes involving a large number of mediator systems, which starts with deficient supply, consumption of high-energy compounds and collapse of energy metabolism, and leads, via excessive release of excitatory neurotransmitters, such as glutamate and aspartate, with limited or absent reuptake, to the pathological increase in concentration of intracellular calcium which is mainly responsible for the cytotoxicity. The fatal disturbance of calcium homeostasis goes hand in hand with other deleterious processes to contribute to the loss of cellular integrity. These include, inter alia, activation of membrane-associated phospholipases and the arachidonic acid metabolism, with formation of free fatty acids and their breakdown by the cyclooxygenase and lipoxygenase reaction pathways to prostaglandins and leukotrienes as mediators of inflammation, the production of aggressive oxygen free radicals with pronounced potential for damage to cell membranes, a drastic rise in membrane permeability, the development of vasogenic and cytotoxic cerebral edemas and the proteolysis, triggered by calcium ions, of protein structures intrinsic to the cell. Since all these mechanisms are time-dependent, there is a latency period between the occurrence of the ischemia and the death of cells of about 6 to a maximum of 12 hours, and medical interventions can have prospects of success only in this time window, if at all (Rev. Med. Interne 1994, 15/5: 350-356).
Attempts at new causal therapies are now concentrated on intervening specifically in the pathogenetic reaction cascade to interrupt, as soon as possible, the progressive course of the acute cerebral ischemia, and thus permanently to control the postischemic neuronal cell loss. At present, essentially two strategies are being followed (Stroke 1990, 21/8 Suppl. 1: 1-130-1-131); on the one hand, thrombolysis of thromboembolic and atherothrombotic blockages with fibrinolytics such as streptokinase, urokinase or recombinant tissue plasminogen activator r-tPA, with the aim of early rechannelization of the arterial system and, on the other hand, cytoprotection aimed at the survival of the neurons under ischemic conditions.
The neuroprotective therapeutic principles which have been intensively investigated, particularly by pharmacologists but, in some cases, also already by clinicians include, for example, suppression of the neuronal calcium influx with calcium antagonists (for example nimodipine, nicardipine, flunarizine and levemopamil), EAA (excitatory amino acid) antagonists (for example competitive and non-competitive NMDA (N-methyl-D-aspartate) and non-NMDA antagonists), or gangliosides (for example GM-1); blockade of the arachidonic acid cascade and elimination of its harmful metabolic products with phospholipase, cyclooxygenase and lipoxygenase inhibitors or PAF (platelet-activating factor), thromboxane and leukotriene antagonists; inhibition of the lipid peroxidation which damages cell membranes using oxygen free radical scavengers (for example superoxide dismutase, catalase, alpha-tocopherol, ascorbic acid, ginkgo leaves, allopurinol, tirilazad and melatonin) or heavy metal chelators (for example deferoxamine); limiting the spread of edema with antiedematous active substances (for example corticosteroids); reducing the tendency to thrombosis with anticoagulants (for example heparin) and platelet aggregation inhibitors (for example ASA, ticlopidine, prostacycline and its more stable synthetic derivatives); and assisting endogenous protective factors with serotonin 1A agonists (for example urapidil and ipsapirone), adenosine modulators (for example propentofylline and vinpocetine) or neurotrophic growth factors (for example transforming growth factor TGF-.beta.1 and brain-derived neurotrophic factor) and their release activators (Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1993, 17/1: 21-70; Clin. Neuropharmacol. 1990, 13 Suppl 3: S9-S25). The greatest prospects of success in this are, of course, ascribed to a multifactorial intervention in the pathogenetic reaction cascade with its complex network of mutually amplifying mediator systems (Drugs 1988, 35/4: 468-476), whether by combining different selectively acting drugs or, more advantageously, by a single drug with the widest possible spectrum of pharmacological effects.
Besides propentofylline (3-methyl-1-(5-oxohexyl)-7-propylxanthine) which has already been mentioned, there have been investigations by pharmacologists to a greater or lesser extent and, in most cases, also by clinicians, of other xanthines, such as the methylxanthines theophylline (1,3-dimethylxanthine), theobromine (3,7-dimethylxanthine and caffeine (1,3,7-trimethylxanthine) which are widespread in nature, and the synthetic 1,3,7-trialkyl derivatives pentoxifylline (3,7-dimethyl-1-(5-oxohexyl)xanthine; Drugs & Aging 1995, 7/6: 480-503) and denbufylline (1,3-dibutyl-7-(2-oxopropyl)xanthine), without a clear therapeutic benefit having been detectable hitherto in the prophylaxis and treatment of acute ischemic stroke. On the contrary, the natural methylxanthines may in fact lead to a deterioration in the clinical situation (Schweiz. Rundsch. Med. Prax. 1989, 78/23: 663-666) and have therefore been said to be contraindicated. Only propentofylline appears to occupy a certain position as an exception, because of its exclusive profile of pharmacological effects, however (Gen. Pharmac. 1994, 25/6: 1053-1058; Drug. Dev. Res. 1993, 28/3: 438-444), although further controlled clinical studies with a sufficiently large number of patients are required in order to be able reliably to assess the therapeutic value of the product (J. Cereb. Blood. Flow Metab. 1993, 13/3: 526-530).